Nitroxyderivatives having antinflammatory, analgesic and antithrombotic activity

Abstract

Organic or inorganic salts of compounds of general formula: A-X1-N(O)z for use as medicaments having anti-inflammatory, analgesic and antithrombotic activity, wherein A is R(COXu)t wherein t is 0 or 1; u is 0 or 1 and X is O, NH, NR1c wherein R1c us a C1-C10 alkyl and R is, for example, (Ia) wherein R1 is acetoxy, preferably in ortho position with respect to -CO- and R2 is hydrogen or acetylsalicylsalicylic acid derivatives; and X1 is the formula (B), Y being a ring containing at least one salified nitrogen atom.

What is claimed is:  
     
       1. A compound of formula 
       
         
           A—X 1 —N(O) z    
         
       
       or an organic or inorganic salt thereof, 
       wherein: 
       z is 1 or 2;  
       A=R(COX u ) t  and wherein t is 0 or 1; u is 0 or 1;  
       X=O, NH, NR 1c  wherein R 1c  is a linear or branched C 1 -C 10  alkyl;                    
        wherein:  
       nIX is an integer between 0 and 3;  
       nIIX is an integer between 1 and 3;  
       R TIX , R TIX′ , R TIIX , R TIIX′ , equal to or different from each other, are H or a linear or branched C 1 -C 4  alkyl;  
       Y is a heterocyclic ring containing at least one salifiable nitrogen atom;  
       R is selected from the groups consisting of:  
       group 1) wherein t=1 and u=1                   
        wherein:  
       R 1  is an OCOR 3  group; R 3  is linear or branched C 1 -C 5  alkyl, or the residue of a heterocycle with a single ring having 5 or 6 atoms which is aromatic, partially or totally hydrogenated, containing one or more hetero-atoms independently selected from O, N and S;  
       R 2  is hydrogen, hydroxyl, halogen, a linear or branched C 1 -C 4  alkyl, a linear or branched C 1 -C 4  alkoxyl, a linear or branched C 1 -C 4  perfluoroalkyl, nitro, amino, mono- or di-(C 2-4 ) alkylamino;  
       nI is 0 or 1;  
       group II) wherein t=1, u=1                   
        wherein  
       R II5  is H, a linear or branched C 1 -C 3  alkyl;  
       R II6  has the same meaning as R II5 , or when R II5  is H R II6  may also be benzyl;  
       R II1 , R II2  and R II3  are each independently hydrogen, a linear or branched C 1 -C 6  alkyl a linear or branched C 1 -C 6  alkoxy, or Cl, F, Br;  
       R II4  is R II1  or bromine;  
       group III) wherein t=1, u=1                   
        wherein:  
       R 2a  and R 3a  are H, a linear or branched, substituted or non-substituted, C 1 -C 12  alkyl or allyl, with the proviso that when one of R 2a  and R 3a  is allyl, the other is H;  
       R 1a  is selected from the group consisting of:                  
                   
       wherein 
       in formula (IV), R III1  is H or SR III3  wherein R III3  contains from 1 to 4 C atoms, linear or branched; R III2  is H or hydroxyl;  
       in formula (XXI), R xxio , is H, a linear or branched alkyl from 1 to 6 C atoms, a C 1 -C 6  alkoxycarbonyl bound to a C 1 -C 6  alkyl, C 1 -C 6  carboxyalkyl, C 1 -C 6  alkanoyl, optionally substituted with halogens, benzyl or halobenzyl, benzoyl or halobenzoyl;  
       R xxi  is H, halogen, hydroxyl, CN, C 1 -C 6  alkyl optionally containing OH groups, C 1 -C 6  alkoxy, acetyl, benzyloxy, SR xxi2  wherein R xxi2  is C 1 -C 6  alkyl; C 1 -C 3  perfluoroalkyl; C 1 -C 6  carboxyalkyl optionally containing OH groups, NO 2 , amino; sulphamoyl, dialkyl suphamoyl with C 1 -C 6  alkyl, or difluoroalkylsulphonyl with C 1 -C 3  alkyl;  
       R xxi1  is halogen, CN, C 1 -C 6  alkyl containing one or more OH groups, C 1 -C 6  alkoxy, acetyl, acetamido, benzyloxy, SR III3  as above defined, C 1 -C 3  perfluoroalkyl, hydroxy, C 1 -C 6  carboxyalkyl, NO 2 , amino, mono- or di-alkyl-amino C 1 -C 6 ; sulphanoyl, dialkyl sulphamoyl C 1 -C 6 , or di-fluoroalkylsulphamoyl as above defined; or R xxi  together with R xxi1  is a C 1 -C 6  alkylene dioxy;  
       in formula (XXXV),  
       Ar is phenyl, hydroxyphenyl optionally mono- or poly-substituted with halogen, C 1 -C 6  alkanoyl and alkoxy, C 1 -C 6  trialkyl, cyclopentyl, cyclohexyl cycloheptyl, heteroaryl, furyl optionally containing OH, pyridyl;  
       group IV) wherein t=1, u=1                   
        wherein:  
       one of R IVd  and R IVd1  is H and the other is H, a linear or branched alkyl from C 1  to C 6 , difluoroalkyl with the alkyl having from 1 to 6 C atoms, or R IVd  and R IVd1  form together a methylene group;  
       R IV  is selected from the group consisting of:                    
       wherein:  
       in formula (II), R iv-ii  is C 1 -C 6  alkyl, C 3 -C 7  cycloalkyl, C 1 -C 7  alkoxymethyl, C 1 -C 3  trifluoroalkyl, vinyl, ethynyl, halogen, C 1 -C 6  alkoxy, difluoroalkoxy with the C 1 -C 7  alkyl, C 1 -C 7  alkoxymethyloxy, alkylthiomethyloxy with the C 1 -C 7  alkyl, alkyl methylthio with the C 1 -C 7  alkyl, cyano, difluoromethylthio, phenyl- or phenylalkyl substituted with the C 1 -C 8  alkyl; in formula (III), R iv-iii  is a C 2 -C 5  alkyl, optionally branched, C 2  and C 3  alkyloxy, allyloxy, phenoxy, phenylthio, cycloalkyl having from 5 to 7 C atoms, optionally substituted in position 1 with a C 1 -C 2  alkyl;  
       group V)                    
       group VE)                    
       wherein in group V)  
       in formula (II), R vii  is H or a linear or branched C 1 -C 4  alkyl; R vii-1  is R vii  or a linear or branched C 1 -C 4  alkoxy; Cl, F, Br; the position of R vii-1  being ortho, or meta, or para;  
        when R is formula (V), A=R and t=0;  
        when R is formula (VII), A is RCO, and t=1 u=0 or t=0;  
        when R is formula (IX), A—R and t=0, or t=1 and u=0;  
        when R is formula (III), A=RCOO, t=1 and u=0 or 1; or t=0;  
        when R is formula (IV), A=RCOO, t=1 and u=1.  
     
     
       2. The compound, organic or inorganic salt according to  claim 1 , wherein in the compounds of formula A—X 1 —N(O) z  z is 2 and nIX and nIIX in the formula (B) of X 1  are integers equal to 1 and R TIX , R TIX′ , R TIIX , R TIIX′  are equal to H. 
     
     
       3. The compound, organic or inorganic salt according to  claim 1 , wherein in the compounds of formula A—X 1 —N(O) z  R, X, u and t of the formula A=R(COX u ) t , and Y in formula (B) of X 1 , have the following meanings: 
       when R is selected from Group I),  
       in the compounds of formula Ia) X is equal to O or NH, R 1  is acetoxy, R 2  is hydrogen; in X 1  R TIX =R TIX′ =R TIIX =R TIIX′ =H, n IX =1 and Y is an aromatic ring having 6 atoms, containing a nitrogen atom, said aromatic ring having the two free valences in position 2 and 6;  
       in the compounds of formula Ib) R 3 =CH 3 , nI=0, X is equal to O, X 1  is as above defined for Ia);  
       in the compounds of formula 1c) X=O and u=1;  
       when R is selected from group II),  
       in the formula lia R IT1 , R II4  are hydrogen and R II2  and R II3  are chlorine in ortho-position with respect to NH; R II5  and R II6  are H, X is equal to O, and X 1  is as above defined for the compounds of formula Ia);  
       when R is selected from group III),  
       when R 1a  is as defined in formula (IV), R III1 , and R III2  are H, R 3a  is H, and R 2a  is methyl, X=O;  
       when R 1a  is as defined in formula (XXI), R xxio  is H, the linking bridge is in position 2, R xxi  is H, R xxi1  is chlorine and is in para position with respect to nitrogen;  
       when R 1a  is as defined in the formula (XXXV), Ar is phenyl, R 3a  is H, R 2a  is methyl and X is O;  
       when R 1a  is as defined in the formula IIIa), R 2a =H, R 3a =CH 3 , u=1 and X=O;  
       when R 1a  is as defined in the formula (XXX), R 2a =H, R 3a =CH 3 , u=1 and X=O;  
       when R 1a  is as defined in the formula (XXXI), R 2a =H R 3a =CH 3 , u=1 and X=O;  
       when R 1a  is as defined in the formula (XXXII), R 2a =R 3a =H, u=1 and X=O;  
       when R 1a  is as defined in the formula (XXXIII), R 2a =R 3a =H, u=1 and X=O,  
       when R 1a  is as defined in the formula (XXXVI), R 2a =H, R 3a =CH 3 , u=1 and X=O;  
       when R 1a  is as defined in the formula (XXXVII), R 2a =R 3a =H, t=1 and X=O;  
       when R 1a  is as defined in the formula (XII), R 2a =R 3a =H, u=1, t=1, X=O; or t=O;  
       when R is selected from group IV),  
       when R IV  is the formula (II), R iv-ii =CH 3 O—, R IVd =H and R IVd1 =CH 3 , X=O and X 1  is as above defined for the compounds of formula Ia);  
       when R IV  is the formula (X), R IVd =H, R IVd1 =CH 3 , X=O and X 1  is as above defined for Ia);  
       when R IV  is the formula (III), R iv-iii  is                    
       and R IVd =H, R IVd1  is CH 3 , X=O and X 1  is as above defined for the compounds of formula Ia);  
       when R is selected from group V,  
       when R is the formula (II), R vii  and R vii-1  are H, and A=R;  
       when R is the formula (X), A=RCO, t=1 and u=0;  
       when R is the formula (XI), A=RCO, t=1 and u=0;  
       when R is the formula (XIII), A=RCO, t=1 and u=0;  
       when R corresponds to the formula (XXXX) or (XXXXI), A=RCO, t=1 and u=0.  
     
     
       4. The compound, organic or inorganic salt according to  claim 1 , wherein Y in formula (B) of X 1  contains one or two nitrogen atoms in the ring and is selected from the following:                  
                   
     
     
       5. The compound, organic or inorganic salt according to  claim 4 , wherein the radical Y of formula (B) of X 1  is Y12 substituted in position 2 and 6. 
     
     
       6. The compound, organic or inorganic salt according to  claim 1 , wherein the organic acids are selected from the group consisting of: oxalic, tartaric, maleic, succinic, citric acids and the inorganic acids from nitric, hydrochloric, sulphoric, phosphoric acids. 
     
     
       7. The compound, organic or inorganic salt according to  claim 1 , wherein R in formula A=R (COX u ) t  is selected from those of group I) and group IV). 
     
     
       8. A method for the treatment of inflammation, said method comprising administration an anti-inflammatory effective amount of a compound, organic or inorganic salt of  claim 1 . 
     
     
       9. A method for anti-thrombotic treatment said method comprising administration to a patient in need thereof an anti-thrombotic effective amount of a compound, organic or inorganic salt of  claim 1 . 
     
     
       10. A method for analgesic treatment of inflammation, said method comprising administration to a patient in need thereof an analgesic effective amount of a compound, organic or inorganic salt of  claim 1 . 
     
     
       11. A method for the treatment of septic shock said method comprising administration to a patient in need thereof an effective amount of a compound, organic or inorganic salt of  claim 1 . 
     
     
       12. Pharmaceutical formulations for oral and parenteral use containing as active principles the compound, organic or inorganic salt of  claim 1 .